Asymmetrie three-component strecker reactions catalyzed by trans-4-hydroxy-L-proline-derived N,N′-dioxides

Article abstract of DOI:10.1002/chem.200800319

Novel trans-4-hydroxy-L-proline-derived N,N′-dioxides have been developed and used as efficient organocatalysts for the one-pot three-component Strecker reaction with an aldehyde, (1,1-diphenyl)methylamine, and TMSCN. Both aromatic and aliphatic aldehydes

Full text of DOI:10.1002/chem.200800319

FULL PAPER
DOI: 10.1002/chem.200800319
Asymmetric Three-Component Strecker Reactions Catalyzed by trans-4-
Hydroxy-l-proline-Derived N,N’-Dioxides
Yuehong Wen,[a] Bo Gao,[a] Yingzi Fu,[a] Shunxi Dong,[a] Xiaohua Liu,[a] and
Xiaoming Feng*[a, b]
Abstract: Novel trans-4-hydroxy-l-pro-
line-derived N,N’-dioxides have been
developed and used as efficient orga-
nocatalysts for the one-pot three-com-
ponent Strecker reaction with an alde-
hyde, (1,1-diphenyl)methylamine, and
TMSCN. Both aromatic and aliphatic
aldehydes were found to be suitable
substrates. The corresponding a-amino
nitriles were obtained in high yields
with up to 95% ee (ee=enantiomeric
excess) under mild conditions. Optical-
ly pure products could be obtained
after a single recrystallization. The cat-
alyst can be easily prepared from trans-
4-hydroxy-l-proline and a diamine in
three steps. Based on the experimental
results and the observed absolute con-
figurations of the products, a possible
transition state has been proposed to
explain the origin of the asymmetric in-
duction.
Keywords: amino acids · asymmet-
ric catalysis · dioxides · multicom-
ponent reactions · Strecker reac-
tions
Introduction
metric three-component Strecker reaction catalyzed by a
chiral zirconium catalyst.[4k,l] Until recently, only two exam-
ples of organocatalytic protocols had been reported by
List[5f] and Feng[5s]. Since multicomponent reactions have
many advantages, such as simplified procedures, mild reac-
tion conditions, high atom economy, and environmental
friendliness, the development of new catalysts for a direct
access to the Strecker products by starting from an alde-
hyde, amine, and a cyanide donor is still the research focus
and target in this field.[3a]
Chiral N-oxide, as a ligand or an organocatalyst, has been
shown to be highly efficient in many asymmetric proce-
dures.[6] Two main types of N-oxide have been developed,
which are tertiary amine-derived N-oxides and pyridine N-
oxides. The pyridine (or quinoline-type) N-oxides are very
popular and successful catalysts of this class; however, the
tertiary amine-derived N-oxides are being increasingly con-
centrated on. Recently, Hoveyda and Snapper reported the
l-proline based mono-N-oxides[7] and Feng developed the
amino acid derived N,N’-dioxides.[8] Herein, we wish to
report a novel trans-4-hydroxy-l-proline-based N,N’-dioxide
and its application in the catalytic asymmetric one-pot
three-component Strecker reaction.
As a result of the significance and the ever-increasing
demand for the a-amino acids in chemistry and biology, the
development of efficient methods for their preparation has
attracted considerable attention.[1] The Strecker reaction,
which was first reported in 1850, represents one of the sim-
plest and most economical methods.[2] In particular, the
asymmetric catalytic Strecker reaction is a highly useful and
desirable strategy. In recent years, considerable effort has
been devoted towards the development of catalytic asym-
metric Strecker reactions.[3] Efficient catalysts are chiral
metal complexes,[4] such as Al, Ti, Zr, and lanthanide com-
pounds, and chiral metal-free compounds[5] that contain gua-
nidines, ureas and thioureas, bis
ACHTREUNG
Brønsted acids, bisformamides, and N-galactosyl aldAHCTREUNG
Among those reports, Kobayashi described the first asym-
[a] Y. Wen, B. Gao, Dr. Y. Fu, S. Dong, Dr. X. Liu, Prof. Dr. X. Feng
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry
Sichuan University, Chengdu 610064 (China)
Fax : (+86)28-8541-8249
E-mail: xmfeng@scu.edu.cn
Our strategy is to design a framework of amino acid de-
rived N,N’-dioxides (Scheme 1) that combine both the Lewis
base (N-oxide) and amide moieties, which can act as a bi-
functional organocatalyst in the Strecker reaction. The two
molecular amino acids are connected together by a carbon
[b] Prof. Dr. X. Feng
State Key Laboratory of Oral Diseases
Sichuan University, Chengdu 610041 (China)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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6789

N,N’-dioxides were chosen as
the organocatalysts for the ini-
tial tests of the one-pot three-
component Strecker reaction
with benzaldehyde, (1,1-diphe-
nyl)methylamine, and TMSCN.
Indeed, high reactivity was ob-
served although the enantiose-
lectivity was not satisfactory.[11]
The W1 N,N’-dioxides used
were prepared by the coupling
of two amino acid units at the
N termini, the backbone of
which may not be beneficial
Scheme 1. The design of N,N’-dioxides.
for good enantioselectivity in
chain at the N termini (type A) or by a diamine at the acid
section (type B). Type A N,N’-dioxides have exhibited their
function in many reactions in our previous studies,[5l,m,8]
this system. Because an amino acid has two reactive func-
tional groups, it is logical to devise a new class of catalyst in
which two prolines are connected at the C termini by a di-
whereas type B N,N’-dioxides coordinated with indium
A
ACHTREaUNG mine. Synthesis of the new backbone of the N,N’-dioxides
have been used primarily for the asymmetric ring opening
is much easier requiring only three steps: 1) reductive ami-
nation, 2) isobutyl chlorocarbonate assisted coupling, and
3) directed amine oxidation.
of meso-epoxides with aromatic amines.[9]
A series of novel N,N’-dioxides was prepared and exam-
ined (Table 1). Catalyst W2 provided the product with
Results and Discussion
The N-substituted a-amino nitriles, in particular, those with
an N-benzhydryl substituent, can be converted into the cor-
responding a-amino acids in one step without loss of enan-
tiomeric excess.[4f,10] In our previous study, a stoichiometric
amount of the chiral quinoline N-oxide was applied to pro-
mote the Strecker reaction between N-benzhydrylimines
and trimethylsilyl cyanide (TMSCN).[5k] Inspired by this re-
search, we presumed that the amino acid based N,N’-diox-
ides, which contained both the N-oxide and amide moieties,
might be more efficient in the Strecker reaction. So the W1
Table 1. Survey of N,N’-dioxides W2–8 in the asymmetric one-pot, three-
component Strecker reaction.[a]
Entry
Catalyst
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
W2
W3
W4
W5
W6
W07
W28
W8
94
88
14
0
9860
97
9860
988
988
8
59
7
8[d]
7
[a] Reagents and conditions: After stirring the mixture of benzaldehyde
(0.2 mmol) and (1,1-diphenyl)methylamine (0.2 mmol) in CH2Cl2
(1.0 mL) for 2 h at 258C, the catalyst was added. Then TMSCN
(0.4 mmol) was added at À208C. [b] Yield of isolated product. [c] Deter-
mined by HPLC analysis (Chiralpak AD-H), and the absolute configura-
tion was established as S by comparison with the literature.[4f,5s] [d] The
preformed imine was used as the substrate.
14% ee (ee=enantiomeric excess); however, W3 gave only
racemic product (Table 1, entries 1 and 2). It might be that
the (S,S)-diamine possessed a better conformation to match
l-proline than the (R,R)-diamine. When replacing the
(1S,2S)-cyclohexane-1,2-diamine with (1S,2S)-1,2-diphenyl-
ethane-1,2-diamine, much better enantioselectivity was ob-
tained (entry 3). By changing the substituents at the N ter-
mini of the pyrrole ring, similar results were obtained with
the isopropyl and 3-pentyl groups (entries 4 and 5). Howev-
er, further enlargement or reduction of the ring size of the
cyclohexyl substituent led to worse enantioselectivity, with
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N,N’-Dioxide-Catalyzed Strecker Reactions
FULL PAPER
40% ee provided by a cycloheptyl or cyclopentyl group.[12]
Encouragingly, 98% yield and 82% ee were gained by re-
placing the l-proline with trans-4-hydroxy-l-proline
(entry 7); the reason for this might be that the hydroxy
group adjusted the steric environment slightly, which was
more favorable for high enantioselectivity. N,N’-Dioxides
W7 and W8 were the optimal catalysts (entries 6 and 7).
The synthesis of W8 was easier than that of W7 in the re-
ductive amination step, so W8 was chosen as the final cata-
lyst. The preformed imine was also used as the substrate
with catalyst W8 (entry 8); however, the results were not as
good as those of the in-situ-generated imine. This showed
that the water released during the condensation of benzalde-
hyde and (1,1-diphenyl)methylamine was important for the
reaction.
Table 2. Optimization of reaction conditions for the asymmetric one-pot,
three-component Strecker reaction.[a]
Entry Solvent
Cat. [mol%] T [8C] t [h] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
Et2O
PhCH3
CHCl3
10
10
10
À20
À20
À20
À20
20
22
10
14
25
90
9842
9828
988
99
90
9860
1
93
99
60
45
ACHTREU(NG CH2Cl)2 10
CH2Cl2
CH3OH
CH2Cl2
2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
10
10
5
20
10
10
10
10
10
À20 2 12
À20
À20
À20
À20
À20
0
10
10
7
0
81
8CH
9[d]
898
12
5
8
10[e]
82
75
90
11[d]
12[d]
13[d]
As mentioned above, one of the advantages of this proto-
col was that the catalyst W8 can be prepared in three steps
in good yield from commercially available optically pure
trans-4-hydroxy-l-proline and (1S,2S)-1,2-diphenylethane-
1,2-diamine (Scheme 2).[7,9] In the first step, compound A
À45
36
93
À0 788 53
34
[a] Reagents and conditions: After stirring the mixture of benzaldehyde
(0.2 mmol) and (1,1-diphenyl)methylamine (0.2 mmol) in solvent
(1.0 mL) for 2 h at 258C, the catalyst W8 was added. Then TMSCN
(0.4 mmol) was added at reaction temperature. [b] Yield of isolated prod-
uct. [c] Determined by HPLC analysis (Chiralpak AD-H). [d] 0.5 mL
CH2Cl2 was used. [e] 1.5 mL CH2Cl2 was used.
tivity in the range from 0.4 to 0.13m (entries 9 and 10). The
temperature effects were also examined (entries 11–13). On
decreasing the temperature from À20 to À458C, the ee
value increased to 90% ee (entry 12); however, a further de-
crease led to very low yield and enantioselectivity
(entry 13). Other parameters were also checked, such as the
effect of additives and the ratio of the three components,
but the results were not further improved. Therefore, the
optimal reaction conditions were selected as: 0.2 mmol of
benzaldehyde, 0.2 mmol of (1,1-diphenyl)-methylamine,
10 mol% of W8, and 0.4 mmol of TMSCN in 0.5 mL of
CH2Cl2 at À458C.
Scheme 2. Synthesis of the chiral catalyst W8 from trans-4-hydroxy-l-pro-
line.
was obtained in nearly quantitative yield by reductive ami-
nation in the presence of cyclohexanone; followed by forma-
tion of amide W9, the reaction of which was completed in
1 h (62% yield); W8 was generated as a single diastereomer
in 86% isolated yield.
Under the optimal conditions, the substrate generality
was examined, and the results are listed in Table 3. Both the
aromatic and aliphatic aldehydes were found to be suitable
substrates for the asymmetric three-component Strecker re-
action. For the aromatic aldehydes, high yields (up to 98%)
and good enantioselectivities (up to 91% ee, up to 99% ee
after a single recrystallization) were achieved (Table 3, en-
tries 1–9). In general, the aromatic ring with electron-donat-
ing substituents exhibited higher reactivity (entries 3 and 4),
whereas the electron-withdrawing substituents showed
better enantioselectivities (entries 5–8). A low yield of 68%
was obtained for 2-nitrobenzaldehyde (entry 2), which was
presumably caused by the steric effect of the ortho-nitro
substituent. 2,4-Dichlorobenzaldehyde provided the product
with 89% ee (entry 8), whereas 96% yield and 91% ee were
obtained with 1-naphthaldehyde (entry 9). A poor ee value
was obtained for the heterocyclic aldehyde of furfural.[15]
For the aliphatic and a,b-unsaturated aldehydes, the catalyt-
ic system was also very efficient (up to 99% yield and
95% ee; entries 10–18). Branched aldehydes represented
very good substrates (entries 13–15), for example, the best
With the optimized catalyst W8 in hand, the reaction con-
ditions were explored. The solvent showed an important
impact on reactivity and selectivity. The ethereal solvents
such as Et2O gave low yield and moderate enantioselectivity
(Table 2, entry 1). Toluene, CH2ClCH2Cl, and CHCl3 provid-
ed good yields, but the enantioselectivities were notably di-
minished (entries 2, 3, and 4). When protic solvents like
CH3OH were used, high yields but racemic products were
afforded (entry 6). CH2Cl2 was the best solvent for the
three-component Strecker reaction (entry 5). The catalyst
loading and substrate concentration effects were investigat-
ed next (entries 7–10). On decreasing the catalyst loading
from 10 to 5 mol%, the ee value was maintained (entry 7).
The enantioselectivity was reduced when the catalyst load-
ing was increased to 20 mol% (entry 8).[13] The substrate
concentration has little effect on reactivity and enantioselec-
Chem. Eur. J. 2008, 14, 6789 – 6795
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6791

X. Feng et al.
Table 3. Scope of the asymmetric one-pot, three-component Strecker re-
action.[a]
Table 4. Control experiment for the mechanistic study.[a]
Entry Cyanide source Cat. [10 mol%] t [h] Yield [%][b] ee [%][c]
1[d]
2
3
4
5
AcCN
W8
W9
W10
W11
W8
40
15
15
15
780
86
96
93
1
TMSCN
TMSCN
TMSCN
TMSCN
0
4
0
898
8
[a] Reagents and conditions: After stirring the mixture of benzaldehyde
(0.2 mmol) and (1,1-diphenyl)methylamine (0.2 mmol) in CH2Cl2
(0.5 mL) for 2 h at 258C, the catalyst was added. Then TMSCN
(0.4 mmol) was added at À208C. [b] Yield of isolated product. [c] Deter-
mined by HPLC analysis (Chiralpak AD-H). [d] The reaction was carried
out at À458C.
signed and performed (Table 4). To determine if the
TMSCN and N-oxide took part in the enantioselectivity-de-
termining step, other cyanide sources and the precursor W9
Entry
1a–r
2a–r
t [h]
Yield [%][b]
ee [%][c]
1
2[f]
3
4
5
1a2a
1b
1c
1d
1e
1 f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
36
80
0 3(969) (
40
72
72
60
60
36
3 36
30
36
36
7 30
36
36
93
68
988
95
90
95
94
82
96
988
96
60
95
988
86
93
87
99
90 (99)[d] (S)[e]
81
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
S)
80 (S)
84 (S)
87 (99) (S)
87 (99)
89
6
7
8[f]
9
91 (99) (S)
10
11
12
13[g]
14
15
16
17
18
of the N,N’-dioxides were examined (Table 4, entries 1 and
2). The results indicated that the cooperation of the silicon-
containing cyanide source and the N-oxide was essential for
catalytic efficiency. Both the diamine-derived and the (S)-
phenylethylamine-derived mono-N-oxides, W10 and W11,
respectively, provided racemic products (entries 3 and 4),
which showed that the presence of two N-oxides together in
one molecule was also a requirement for asymmetric induc-
tion. According to the above phenomena and the previous
81
80
90
95
80
72
84
40
32
[a] Reagents and conditions: After stirring the mixture of aldehyde
(0.2 mmol) and (1,1-diphenyl)methylamine (0.2 mmol) in CH2Cl2
(0.5 mL) for 2 h at 258C, the catalyst W8 was added. Then TMSCN
(0.4 mmol) was added at À458C. [b] Yield of isolated product. [c] Deter-
mined by HPLC analysis (Chiralpak AD-H or AS-H). [d] After a single
recrystallization. [e] The absolute configuration was established as S by
comparison with the literature.[4e,f,5k,s,14] [f] The reaction was carried out at
À208C. [g] 15 mol% W8 was used.
studies on N,N’-dioxides[7,8,9,16] and cyanosilylation,[5k–m,s]
a
possible transition state was proposed as illustrated in
Figure 1. The two N-oxides coordinated to silicon at the
same time to form a hypervalent silicate species whereby a
fixed chiral pocket was created; meanwhile, the in-situ-gen-
erated imine was activated by a hydrogen bond between the
nitrogen of the imine and the hydrogen of the amide. The
Re face is much more accessible than the Si face, as in-
creased repulsion between the phenyl groups of the imine
and diamine occurs in TS2. Hence, the S product was
smoothly produced according to favorable TS1. However,
the real mechanism and the function of the hydroxy groups
are unclear and are being studied.
enantioselectivity was obtained with 2-ethylbutanal
(entry 15). In the case of the most challenging a-unbranched
aldehydes, slightly lower enantioselectivities were observed
(entries 11 and 12). A high yield and good ee value were
also given by a cyclic aldehyde (entry 18). Accordingly, a
larger substrate scope, better enantioselectivities, and the
opposite S isomers were achieved with these N,N’-dioxides
compared with our previously reported bisformamide cata-
lysts.[5s]
Conclusion
To elucidate the mechanism of the trans-4-hydroxy-l-pro-
line-based N,N’-dioxide-catalyzed one-pot three-component
Strecker reaction, a series of control experiments were de-
trans-4-Hydroxy-l-proline-based N,N’-dioxides have been
developed to catalyze the one-pot, three-component Streck-
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N,N’-Dioxide-Catalyzed Strecker Reactions
FULL PAPER
Isobutyl chlorocarbonate (0.27 mL, 2.05 mmol) and Et3N (0.3 mL,
2.2 mmol) were added to a solution of the unpurified acid (437 mg,
2.05 mmol) in CH2Cl2 (30 mL) at 08C. After 20 min, (1S,2S)-diphenyl-
ethane-1,2-diamine (212 mg, 1 mmol) was added and the mixture was al-
lowed to stir at room temperature for 1 h. The solution was washed with
saturated aqueous NaHCO3 (20 mL) and brine (20 mL), dried over anhy-
drous MgSO4, and concentrated to give a crude product. The crude prod-
uct was purified by silica gel chromatography (CH3OH/ethyl acetate
1:20) to give the pure amide W9 (374 mg, 62% yield). M.p. 114–1168C;
1
[a]1D0 =À55.9 (c=0.1 in CH2Cl2); H NMR (400 MHz, CDCl3): d=8.29 (d,
J=7.6 Hz, 2H), 7.28–7.19 (m, 6H), 7.08–7.06 (m, 4H), 5.33 (d, J=6.8Hz,
2H), 4.11 (dd, J=9.6, 5.2 Hz, 2H), 3.54 (dd, J=9.2, 5.2 Hz, 2H), 3.17
(dd, J=9.6, 5.2 Hz, 2H), 2.62 (dd, J=9.6, 6.0 Hz, 2H), 2.32 (s, 2H), 2.12–
1.65 (m, 16H), 1.28–1.13 ppm (m, 10H); 13C NMR (100 MHz, CDCl3):
d=175.0, 138.9, 128.4, 127.6, 127.0, 70.2, 62.8, 60.8, 57.2, 55.6, 39.7, 32.6,
28.0, 26.0, 25.9, 25.4 ppm; HRMS (ESI): m/z calcd for C36H51N4O4:
603.3910 [M+H]+; found: 603.3910.
mCPBA (mCPBA=3-chloroperbenzoic acid) (278mg, 1.36 mmol) was
added to a solution of the amide W9 (374 mg, 0.62 mmol) in CH2Cl2
(20 mL) at À208C. The mixture was allowed to stir at À208C for 40 min.
Then, the reaction was warmed to room temperature and purified by
silica-gel chromatography (ethyl acetate/CH3OH 3:1, 2:1, and 1:1) to give
pure W8 as a white solid (338mg, 86%). M.p. 156–159 8C; [a]1D0 =À28.0
(c=0.1 in CH3OH); 1H NMR (400 MHz, CDCl3): d=11.47, 11.01, 9.44 (s,
d, d, J=6.6, 9.0 Hz, 2H), 7.41–7.27 (m, 10H), 5.64 (dd, J=8.0, 4.8 Hz,
1H), 5.53 (dd, J=7.2, 4.8Hz, 1H), 4.80 (d, J=5.6 Hz, 1H), 4.56 (d, J=
8.0 Hz, 1H), 4.31–4.28 (m, 1H), 4.10–4.06 (m, 1H), 3.83 (dd, 10.8, 5.2 Hz,
1H), 3.74–3.68(m, 2H), 3.55–3.35 (m, 5H), 3.24–3.20 (m, 3H), 2.82–2.74
(m, 3H), 2.40–2.05 (m, 6H), 1.92–0.91 ppm (m, 12H); 13C NMR
(100 MHz, [D6]DMSO): d=169.0, 168.9, 168.7, 141.1, 140.9, 140.0, 128.4,
128.35, 128.2, 127.6, 127.5, 127.2, 127.1, 79.0, 75.1, 74.5, 72.5, 70.8, 70.6,
70.0, 68.9, 66.6, 60.7, 57.5, 49.1, 31.8, 27.1, 26.6, 25.2, 19.3, 14.3 ppm;
HRMS (ESI): m/z calcd for C36H51N4O6: 635.3809 [M+H]+; found:
635.3809.
l-Proline-based N,N’-dioxides W2:[9] White solid; [a]D25 =À16.4 (c=0.39
in CH2Cl2); 1H NMR (600 MHz, CDCl3): d=11.42 (brs, 2H), 3.90 (m,
2H), 3.69 (m, 2H), 3.42–3.35 (m, 4H), 3.33–3.24 (m, 2H), 2.56–2.54 (m,
2H), 2.45–2.35 (m, 7H), 2.18(m, 4H), 2.04–2.01 (m, 2H), 1.94–1.81 (m,
8H), 1.69–1.67 (m, 2H), 1.51–1.34 (m, 9H), 1.15–1.12 ppm (m, 2H);
13C NMR (100 MHz, CDCl3): d=167.6, 77.2, 74.8, 71.8, 64.5, 49.5, 30.9,
28.8, 28.4, 27.8 (27.82), 27.8 (27.75), 25.3, 25.2 (25.25), 25.2 (25.19), 22.4,
19.9 ppm.
Figure 1. Proposed transition states TS1 and TS2.
er reaction with an aldehyde, (1,1-diphenyl)methylamine,
and TMSCN. The novel organocatalyst is efficient for a
broad variety of aromatic and aliphatic aldehyde substrates,
leading to the corresponding products in excellent enantio-
selectivities (up to 95% ee). The catalyst is easily prepared
from trans-4-hydroxy-l-proline. A possible transition state
(TS1) has been proposed to explain the origin of asymmetric
induction. Further investigations are focused on the explora-
tion of related catalyst libraries, the detailed mechanism,
and extension of the reaction scope.
l-Proline-based N,N’-dioxides W3:[9] Hygrometric white foam; [a]2D5
=
1
À30.5 (c=0.44 in CH2Cl2); H NMR (400 MHz, CDCl3): d=10.91 (d, J=
7.2 Hz, 2H), 3.78(m, 2H), 3.64–3.59 (m, 2H), 3.44–3.40 (m, 2H), 3.26–
3.21 (m, 2H), 3.10–3.04 (m, 2H), 2.40–2.35 (m, 9H), 2.17–2.08(m, 2H),
1.99–1.96 (m, 2H), 1.90–1.87 (m, 8H), 1.71–1.62 (m, 6H), 1.59–1.52 (m,
3H), 1.36–1.31 (m, 4H), 1.15–1.11 ppm (m, 2H).
Experimental Section
General: 1H and 13C NMR spectra were recorded in CDCl3 or
[D6]DMSO on commercial apparatus. TMS served as internal standard
(d=0 ppm) for 1H NMR and CDCl3 was used as internal standard (d=
77.0 ppm) for 13C NMR; the coupling constants J are given in Hz. Chemi-
cal shifts are reported in ppm with the solvent reference as the internal
standard (CHCl3: d=7.26 ppm). HPLC analysis was performed on a
chiral column (Daicel Chiralpak AD-H or AS-H column). Optical rota-
tions were reported as follows: [a]TD (c g/100 mL, in solvent). HRMS
were recorded on a commercial apparatus (ESI or ES Source). Melting
points were measured on an electrothermal digital melting point appara-
tus. Unless otherwise indicated, all materials were obtained from com-
mercial sources, and used as purchased without dehydration, except for
aldehydes, which were distilled before use. Solvents for reactions were
dried and distilled prior to use according to the standard methods.
l-Proline-based N,N’-dioxides W4:[9] White solid; m.p. 134–1368C;
1
[a]2D5 =À48.7 (c=1.41 in CH2Cl2); H NMR (400 MHz, CDCl3): d= 11.81
(d, J=5.6 Hz, 2H) 7.46–7.44 (m, 4H), 7.38–7.34 (m, 5H), 7.33–7.22 (m,
2H), 5.44–5.42 (m, 2H), 3.60–3.55 (m, 2H), 3.47–3.42 (m, 2H), 3.22–3.11
(m, 3H), 2.73–2.66 (m, 4H), 2.50 (m, 2H), 2.40–2.38(m, 3H), 2.17–2.14
(m, 2H), 1.92–1.90 (m, 2H), 1.82–1.79 (m, 3H), 1.73–1.71 (m, 2H), 1.67–
1.61 (m, 2H), 1.55–1.54 (m, 2H), 1.40–1.31 (m, 2H), 1.01–0.96 ppm (m,
4H); 13C NMR (100 MHz, CDCl3): d=168.8, 139.7, 128.5, 127.2, 126.5,
75.2, 72.3, 65.3, 58.0, 28.4, 27.4, 26.6, 25.1, 24.9, 24.7, 19.8 ppm; HRMS
(ESI) m/z: calcd for C36H51N4O4: 603.3910 [M+H]+; found: 603.3910.
l-Proline-based N,N’-dioxides W5: White solid; m.p. 148–1498C; [a]D10
=
1
À63.0 (c=0.10 in CH2Cl2); H NMR (400 MHz, CDCl3): d=11.87 (d, J=
6.8Hz, 2H), 7.48–7.44 (m, 4H), 7.36–7.28 (m, 4H), 7.24–7.20 (m, 2H),
5.67–5.65 (m, 2H), 3.62–3.57 (m, 2H), 3.29–3.25 (m, 2H), 3.25–3.14 (m,
2H), 2.78–2.64 (m, 4H), 2.46–2.36 (m, 4H), 1.92–1.88 (m, 2H), 1.23 (dd,
J=6.0, 3.6 Hz, 6H), 1.02 ppm (d, J=6.4 Hz, 6H); 13C NMR (100 MHz,
CDCl3): d=168.0, 139.5, 128.4, 127.0, 126.5, 72.1, 66.3, 62.1, 56.8, 28.1,
19.7, 17.7 ppm; HRMS (ESI): m/z: calcd for C30H43N4O4 523.3279
[M+H]+; found: 523.3268.
Typical procedure for the preparation of catalyst W8: Palladium on
carbon (10% by wt, dry, 0.12 g) was suspended in methanol (10 mL) in a
dry 50 mL flask, which was flushed with N2. trans-4-Hydroxy-l-proline
(1.31 g, 10 mmol) and cyclohexanone (1.2 mL, 11 mmol) were added to
this suspension. The flask was charged with H2 and was kept under a bal-
loon of H2 for 12 h. At this time, the reaction was purged with N2 and fil-
tered through Celite. Removal of the methanol under reduced pressure
led to the unpurified acid (2.09 g, 98% unpurified yield).
Chem. Eur. J. 2008, 14, 6789 – 6795
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6793

X. Feng et al.
l-Proline-based N,N’-dioxides W6: White solid; m.p. 132–1348C; [a]D10
=
1650; d) M. Arend, Angew. Chem. 1999, 111, 3047–3049; Angew.
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À51.0 (c=0.10 in CH2Cl2); 1H NMR (400 MHz, CDCl3): 11.92 (d, J=
6.0 Hz, 2H), 7.43–7.41 (m, 4H), 7.35–7.31 (m, 4H), 7.24–7.20 (m, 2H),
5.61 (d, J=7.2 Hz, 2H), 3.66–3.62 (m, 2H), 3.40–3.35 (m, 2H), 3.22–3.19
(m, 2H), 2.65–2.61 (m, 4H), 2.60–2.10 (m, 4H), 2.09–1.87 (m, 4H), 1.52–
1.38(m, 6H), 0.92 (t, J=7.2 Hz, 6H), 0.74 ppm (t, J=7.2 Hz, 6H);
13C NMR (100 MHz, CDCl3): 168.3, 139.6, 128.5, 127.1, 126.5, 78.1, 72.2,
64.2, 57.0, 28.1, 22.1, 21.9, 19.9, 11.9, 11.1 ppm; HRMS (ESI) m/z calcd
for C34H51N4O4: 579.3910 [M+H]+; found: 579.3910.
trans-4-Hydroxy-l-proline-based N,N’-dioxides W7: White solid; m.p.
126–1288C; [a]1D0 =À18.9 (c=0.12 in CH3OH); 1H NMR (400 MHz,
CDCl3): 11.56, 10.78, 9.46 (s, s, d, J=9.6 Hz, 2H), 7.48–7.27 (m, 10H),
5.86 (dd, J=9.6 ,4.0 Hz, 1H), 5.70 (dd, J=10.0, 4.4 Hz, 1H), 4.80 (d, J=
6.0 Hz, 1H), 4.60 (d, J=7.2 Hz, 1H), 4.24 (t, J=6.0 Hz, 1H), 3.86 (dd,
J=10.8, 5.2 Hz, 1H), 3.80–3.60 (m, 2H), 3.42 (d, J=10.8Hz, 2H), 3.18–
3.06 (m, 4H), 2.35–2.18 (m, 4H), 1.87–1.83 (m, 2H), 1.50–1.40 (m, 6H),
1.03–0.67 ppm (m, 12H); 13C NMR (100 MHz, [D6]DMSO): 168.8, 168.0,
167.8, 140.5, 140.2, 139.4, 128.0, 127.8, 127.2, 127.0, 126.7, 126.66, 79.0,
78.2, 77.4, 73.3, 72.2, 69.9, 69.3, 66.2, 56.2, 55.0, 48.6, 38.3, 22.1, 21.7, 21.6,
12.3, 11.1, 10.0 ppm; HRMS (ESI): m/z: calcd for C36H51N4O4: 611.3809
[M+H]+; found: 611.3808.
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trans-4-Hydroxy-l-proline-based mono-N-oxide W10: White solid;
m.p. 120–1228C; [a]1D0 =À42.0 (c=0.11 in CH2Cl2); 1H NMR (400 MHz,
CDCl3): 11.29 (s, 1H), 8.03 (s, 1H), 7.22–7.14 (m, 10H), 5.32–5.23 (m,
2H), 4.63 (s, 1H), 4.25–4.24 (m, 1H), 3.67–3.64 (m, 2H), 3.52–3.45 (m,
4H), 3.30–3.20 (m, 1H), 3.11 (s, 1H), 2.25–1.32 (m, 10H), 1.30–0.84 ppm
(m, 16H); 13C NMR (100 MHz, CDCl3): 175.6, 168.3, 138.9, 138.5, 128.7,
128.5, 128.3, 127.7, 127.5, 126.5, 126.4, 75.4, 72.6, 71.7, 71.1, 69.5, 66.8,
63.0, 61.8, 61.2, 57.9, 57.3, 56.1, 39.2, 31.6, 29.7, 28.5, 27.5, 26.8, 25.6, 25.4,
25.0, 24.8, 19.3, 13.9 ppm; HRMS (ESI): m/z: calcd for C36H51N4O5:
619.3859 [M+H]+; found: 619.3858.
trans-4-Hydroxy-l-proline-based mono-N-oxide W11: White solid;
m.p. 62–648C; [a]1D0 =À83.7 (c=0.14 in CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=11.17 (m, 1H), 7.29–7.23 (m, 4H), 7.20–7.15 (m, 1H), 5.03–
5.00 (m, 1H), 4.70–4.68(m, 1H), 4.02 (dd, J=12.0, 6.4 Hz, 1H), 3.56 (dd,
J=11.6, 6.8Hz, 1H), 3.41–3.39 (m, 1H), 3.19 (dd, J=11.6, 4.8Hz, 1H),
2.93–2.90 (m, 1H), 2.78–2.76 (m, 1H), 2.26 (dd, J=13.2 ,6.4 Hz, 1H),
2.16–2.13 (m, 1H), 1.89–1.86 (m, 1H), 1.70–1.63 (m, 2H), 1.51–1.49 (m,
1H), 1.42 (d, J=6.8Hz, 3H), 1.31–0.86 ppm (m, 5H); 13C NMR
(100 MHz, CDCl3): 167.4, 143.3, 128.5, 127.2, 126.3, 75.8, 73.8, 70.9, 67.0,
48.5, 39.2, 27.5, 27.4, 25.3, 25.1, 25.0, 22.0 ppm; HRMS (ESI): m/z: calcd
for C19H29N2O3: 333.2178[ M+H]+; found: 333.2179.
General procedure for the catalytic asymmetric one-pot, three-compo-
nent Strecker reaction: Benzaldehyde (21 mL, 0.2 mmol) and (1,1-diphe-
nyl)methylamine (36 mL, 0.2 mmol) were combined in a dry test tube.
Then 0.2 mL CH2Cl2 was added to the mixture and the reaction solution
was stirred at 258C for 2 h. After that, catalyst W8 (10 mol%) and
CH2Cl2 (0.3 mL) were added. The test tube was cooled to À208C,
TMSCN (54 mL, 0.4 mmol) was added, and the mixture was stirred for
8 h at À208C. The crude material was purified by flash chromatography
on silica gel (Et2O/light petroleum ether 1:60) to afford the product 2a in
81%ee as determined by chiral HPLC analysis (Chiralpak AD-H).
Acknowledgements
We thank the National Natural Science Foundation of China (Nos.
20602025 and 20732003) and the Ministry of Education (No.
20070610019) for financial support. We also thank Sichuan University
Analytic & Testing Centre for NMR analysis and the State Key Labora-
tory of Biotherapy for HRMS analysis.
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6794
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Chem. Eur. J. 2008, 14, 6789 – 6795

N,N’-Dioxide-Catalyzed Strecker Reactions
FULL PAPER
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[12] 97% yield and 40% ee were obtained for the catalyst with cyclopen-
tyl groups at the N-temini of the pyrrole ring; 96% yield and
40% ee were obtained for the catalyst with cycloheptyl groups at
the N termini of pyrrole ring.
[13] The phenomena that the enantioselectivity decreased with the in-
crease of catalyst loading is consistent with our previous reports on
the Strecker reaction employing the amino acid derived N,N’-diox-
ides (see references [5l] and [8i]). This may be attributed to the pos-
sibility that TMSCN could be activated by N-oxides from different
N,N’-dioxides making it disadvantageous to generate the favorable
transition state.
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Received: February 21, 2008
Published online: June 12, 2008
Chem. Eur. J. 2008, 14, 6789 – 6795
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6795